Karshi raspolozhen na zapadnoi okraine Pamiro-Alaiskoi gornoi sistemy, v Karshinskom oazise, na reke Kashkadya, u podnozhia vozvyshennosti Kungurtau, v vostochnoi chasti Karshinskoi stepi. Klimat zasushlivyi, osadkov - 200-400 mm v god. Gorod nahoditsya v 400 km k yugo-zapadu ot Tashkenta (520 po doroge). V 10 km vostochnie Karshi raspolozhena voenno-vozdushnaya baza Karshi-Khanabad.